COX-2 is an inducible enzyme expressed in inflammatory neoplastic and neuronal cells. It occupies a central position in synthesizing prostaglandins and thromboxane A2. Several prostaglandins such as prostaglandin E2 and E2 mediate inflammation. Selective inhibition of COX-2 suppresses inflammatory reactions and pain. Selective COX-2 inhibitors such as Celebrex® and Vioxx® prove to be efficacious anti-inflammatory drugs with less adverse effects than other nonsteroidal anti-inflammatory drugs. COX-2 has recently been shown to be causally associated with adenomatous polyposis, a precancerous hereditary disorder and colon cancer. Selective COX-2 inhibitors not only suppress experimental adenomatous polyposis and colon cancer in mice and rats but also reduce human adenomatous polyposis in a randomized clinical trial. However, the extent of polyp reduction by Celebrex® from this clinical trial was small, about 30%, suggesting the involvement of other factors. COX-2 causes cancer growth by several possible mechanisms. COX-2 overexpression in the stromal cells within a cancer mass induces new blood vessel formation (angiogenesis) which provides nutrition for tumor cell growth. COX-2 overexpression increases synthesis of metalloproteinase inhibitors which promotes cancer cell metastasis. It has also been reported that COX-2 stimulates cell proliferation. In summary, COX-2 plays a key role in inflammation, tissue injury and cancer growth.
iNOS (also known as NOS 2) is also an inducible enzyme expressed in macrophages, smooth muscle cells and liver cells. It catalyzes the synthesis of a large quantity of nitric oxide (NO) which forms peroxynitrite with superoxide. Peroxynitrite causes tissue injury and apoptosis. Reactive nitrogen species are also formed from NO, which also causes tissue damage. Proteins and DNA can be nitrosylated by NO. iNOS has been shown to play a key role in the pathogenesis of septic stroke, stroke, myocardial infarction, inflammation. NO can also induce angiogenesis thereby increasing tumor cell growth. Several classes of inhibitors of nitric oxide synthase are available but they are not isoform specific. There is an active research effort to develop iNOS-specific inhibitors.
COX-2 and iNOS are induced concurrently when cells and tissues are stimulated with certain environmental insults. They can be expressed in the same cells or in different cells located within the same affected tissues. Their products act in a concerted manner to promote inflammation, tissue injury, septic shock and tumorigenesis. Treatment for these important human diseases relies on drugs that inhibit a single mediator of the complex pathophysiological processes, and so far has had only limited successes.